Wnt4 protein plays a vital role in muscle regeneration

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One of the many effects of aging is loss of muscle mass, which contributes to disability in older people. To counter this loss, scientists at the Salk Institute are studying ways to accelerate the regeneration of muscle tissue, using a combination of molecular compounds that are commonly used in stem-cell research.

In a study published on May 25, 2021, in Nature Communications, the investigators showed that using these compounds increased the regeneration of muscle cells in mice by activating the precursors of muscle cells, called myogenic progenitors.

Although more work is needed before this approach can be applied in humans, the research provides insight into the underlying mechanisms related to muscle regeneration and growth and could one day help athletes as well as aging adults regenerate tissue more effectively.

“Loss of these progenitors has been connected to age-related muscle degeneration,” says Salk Professor Juan Carlos Izpisua Belmonte, the paper’s senior author. “Our study uncovers specific factors that are able to accelerate muscle regeneration, as well as revealing the mechanism by which this occurred.”

The compounds used in the study are often called Yamanaka factors after the Japanese scientist who discovered them. Yamanaka factors are a combination of proteins (called transcription factors) that control how DNA is copied for translation into other proteins. In lab research, they are used to convert specialized cells, like skin cells, into more stem-cell-like cells that are pluripotent, which means they have the ability to become many different types of cells.

This shows progenitor cells
Induction of Yamanaka factors (OKSM) in muscle fibers increases the number of myogenic progenitors. Top, control; bottom, treatment. Red-pink color is Pax7, a muscle stem-cell marker. Blue indicates muscle nuclei. Credit: Salk Institute

“Our laboratory previously showed that these factors can rejuvenate cells and promote tissue regeneration in live animals,” says first author Chao Wang, a postdoctoral fellow in the Izpisua Belmonte lab. “But how this happens was not previously known.”

Muscle regeneration is mediated by muscle stem cells, also called satellite cells. Satellite cells are located in a niche between a layer of connective tissue (basal lamina) and muscle fibers (myofibers).

In this study, the team used two different mouse models to pinpoint the muscle stem-cell-specific or niche-specific changes following addition of Yamanaka factors. They focused on younger mice to study the effects of the factors independent of age.

In the myofiber-specific model, they found that adding the Yamanaka factors accelerated muscle regeneration in mice by reducing the levels of a protein called Wnt4 in the niche, which in turn activated the satellite cells. By contrast, in the satellite-cell-specific model, Yamanaka factors did not activate satellite cells and did not improve muscle regeneration, suggesting that Wnt4 plays a vital role in muscle regeneration.

According to Izpisua Belmonte, who holds the Roger Guillemin Chair, the observations from this study could eventually lead to new treatments by targeting Wnt4.

“Our laboratory has recently developed novel gene-editing technologies that could be used to accelerate muscle recovery after injury and improve muscle function,” he says. “We could potentially use this technology to either directly reduce Wnt4 levels in skeletal muscle or to block the communication between Wnt4 and muscle stem cells.”

The investigators are also studying other ways to rejuvenate cells, including using mRNA and genetic engineering. These techniques could eventually lead to new approaches to boost tissue and organ regeneration.


Muscle stem cells or satellite cells (SCs) are essential for the regenerative capacity of skeletal muscle. SCs reside in a quiescent and immotile state wedged between the basal lamina and the sarcolemma of the muscle fiber (the niche) (Bischoff, 1990). In response to injury, SCs exit this dormant state and transition toward activation, which includes metabolic activation, cell-cycle entry, and migration. Once dividing, the majority of SCs differentiate, while a subset self-renew to restore the quiescent SC pool.

The quiescent state is critical to maintain stem cell capacity across different niches (Cheung and Rando, 2013, Orford and Scadden, 2008). In contexts of increased SC turnover such as in muscular dystrophy, aging, or in transgenic mice harboring cell-cycle mutations, SC function is impaired (Brack and Muñoz-Cánoves, 2016, Brack and Rando, 2007, Chakkalakal et al., 2014)

For many years, SC quiescence has been considered to be a reversible but homogeneous state, denoted by the absence of proliferation and regulated by cell intrinsic regulators (Bjornson et al., 2012, Boonsanay et al., 2016, Cheung et al., 2012, Mourikis et al., 2011). A quiescent intermediate state referred to as GAlert was characterized (Rodgers et al., 2014).

This transition state is metabolically active, is dependent on mTORC1, and can be induced by systemic hepatocyte growth factor activator (HGFA; Rodgers et al., 2014, Rodgers et al., 2017). SCs in GAlert enter the cell cycle more rapidly, mount a more efficient regeneration process, and retain stem cell capacity. The mechanisms that promote or repress the transition from quiescence to activation are not well understood.

The niche is a conserved regulator of stem cell quiescence and maintenance. A fundamental but unanswered question in stem cell biology is the identity of specific cell types and paracrine-acting factors that control quiescence and the transition toward activation. The Wnt signaling pathway has been demonstrated to act as a conserved regulator of stem cell function via canonical (β-catenin) and non-canonical (planar cell polarity [PCP] and calcium) signaling (Clevers et al., 2014).

However, there is a dearth of information addressing the requirement of specific Wnt ligands, in part due to the possible redundancy between the 19 family members. Recent studies have disrupted Wnt activity using Porcupine (Porcn) or Wntless loss of function alleles in different tissues to disrupt the processing of the Wnt ligand family (Nabhan et al., 2018, Tammela et al., 2017, Zepp et al., 2017).

While these studies provide proof of principle for the importance of Wnt ligands, they did not elucidate the identity of the Wnt family members. Wnt signaling plays a critical role in coordinating SC state transitions from asymmetric fate, proliferation, commitment, and differentiation (Brack et al., 2008, Brack et al., 2009, Jones et al., 2015, Lacour et al., 2017, Le Grand et al., 2009, Parisi et al., 2015b, Rudolf et al., 2016).

Whether Wnt ligands, from an anatomically defined niche cell, control SC quiescence remains unknown. Identifying the niche and signaling molecules that regulate quiescence is critical to understanding regenerative biology and the development of therapeutics to harness stem cell function.

Using an inducible genetic approach to specifically target the SC niche, we provide the first evidence of a paracrine-acting niche factor, Wnt4, that reinforces SC quiescence through activation of Rho-GTPase and repression of YAP (yes-associated protein). In conclusion, Wnt4 levels dictate the depth of SC quiescence during homeostasis, their activation response, and regenerative potential.

reference link: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(19)30342-X?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS193459091930342X%3Fshowall%3Dtrue


In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche” by Chao Wang, Ruben Rabadan Ros, Paloma Martinez-Redondo, Zaijun Ma, Lei Shi, Yuan Xue, Isabel Guillen-Guillen, Ling Huang, Tomoaki Hishida, Hsin-Kai Liao, Estrella Nuñez Delicado, Concepcion Rodriguez Esteban, Pedro Guillen-Garcia, Pradeep Reddy & Juan Carlos Izpisua Belmonte. Nature Communications

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